Process for the production of arylalkanone and intermediate

ABSTRACT

A process for producing 2-methyl-2-phenyl-4-hexanone comprising reacting the Grignard reagent having the structure: ##STR1## with propianic anhydride having the structure: ##STR2##

This is a divisional of application for U.S. Letters Patent Ser. No.188,563 filed on Sept. 18, 1980, now U.S. Pat. No. 4,298,542 issued onNov. 3, 1981.

BACKGROUND OF THE INVENTION

The compound 2-methyl-2-phenyl-4-hexanone having the structure: ##STR3##is well known as having an outstanding rose fragrance. Thus, the U.K.Pat. No. 1,105,455 discloses the use of this material in perfumery andfurther indicates that a process can be use to prepare this material byreacting an acyl chloride with the Grignard reagent having thestructure: ##STR4## Indeed, United Kingdom patent specification No.1,105,455 specifically discloses the reaction: ##STR5## and indicatesthat such reaction preferably takes place in the precense of cadiumchloride. United Kingdom patent specification No. 1,105,455 however,does not actually exemplify such a reaction and further does not aludeto the unexpected, unobvious and advantageous increase in yield bycarrying out the alternative reaction of our invention using propianicanhydride and the Grignard reagent having the structure: ##STR6## andfurther does not indicate the advantage from a yield standpoint of firstreacting the Grignard reagent having the structure: ##STR7## withmanganese chloride to form the novel intermediate having the structure:##STR8## and then reacting the said intermediate having the structure:##STR9## with propionyl chloride having the structure: ##STR10##

Although the generic reaction of an acyl anhydride with an alkylmagnesium halide to form a ketone is well known in organic chemistry,that is the reaction: ##STR11## as it is indicated by Newman & Smith atJ. Org. Chem. 13, 592-8 (1948) wherein R is methyl and R' may besecondary butyl, tertiary butyl, n-butyl or phenyl, the reaction of asterically hindered Grignard reagent with an acyl anhydride or theunexpected, advantageous improvement in yield by first forming themangenese organometallic intermediate from the Grignard reagent and thenreacting it with an acyl chloride is not so taught in the prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 sets forth the GLC profile for the reaction product (crude priorto distillation) of Example I.

FIG. 2 sets forth the GLC profile for fractions 5-10 of the fractionaldistillation product of the reaction product of Example I.

DETAILED DESCRIPTION OF THE DRAWINGS

In FIG. 1, the GLC profile is attained by passing the reaction productthrough a 10% SE-30, 10 foot×1/8 inch GLC column programmed at 100° C.up to 220° C. at 10° C. per minute.

Peak 1 is the peak for the tetrahydrofuran solvent, tetrahydrofuranhaving the structure: ##STR12##

Peak 2 is the peak representing the toluene solvent.

Peak 3 is the peak representing the solvent for propionic anhydridereactant having the structure: ##STR13##

Peak 4 is the peak representing t-butyl benzene having the structure:##STR14##

Peak 5 is the peak representing "neophyl" chloride having the structure:##STR15##which is 2-methyl-2-phenyl-1-chloropropane.

Peak 6 is the peak representing the reaction product2-methyl-2-phenyl-4-hexanone having the structure: ##STR16##

Peak 7, in FIG. 1, represents the dimerization product having thestructure: ##STR17##

In FIG. 2, the peak designated by the number 8 is2-methyl-2-phenyl-4-hexanone having the structure: ##STR18##Theconditions for producing the GLC profile of FIG. 2 are identical tothose conditions used in producing the GLC profile for FIG. 1.

THE INVENTION

The present invention provides a simple economic and efficient processfor producing 2-methyl-2-phenyl-4-hexanone having the structure:##STR19##as well as intermediates for preparing same. The process of myinvention involves carrying out the reaction of "neophyl chlorideGrignard reagent" having the structure: ##STR20##with either propionicanhydride having the structure: ##STR21##or with manganese chloride toform the compound: ##STR22##followed by reaction with propionyl chloridehaving the structure: ##STR23##to form the compound having thestructure: ##STR24##2-methyl-2-phenyl-4-hexanone.

In the reaction of the Grignard having the structure: ##STR25##withpropionic anhydride having the structure: ##STR26##the reaction sequenceis as follows: ##STR27##in this reaction, the addition mode may be oneof two alternative modes; (i) addition of the propionic anhydride to theGrignard reagent or (ii) addition of the Grignard reagent to thepropionic anhydride or mixture of propionic anhydride and cuprouschloride (Cu₂ Cl₂, used as a catalyst). The reaction may take place inthe presence of a cuprous chloride catalyst or in the absence of suchcuprous chloride catalyst. Themole ratio of propionic anhydride:Grignardreagent having the structure: ##STR28##may vary from 0.5:1 up to about2:1 with a preferred mole ratio range of propionic anhydride:Grignardreagent being from 0.9:1 up to 1.3:1. The temperature of reaction mayvary from -23° C. up to 10° C. with a temperature of reaction of -10° C.up to 0° C. being preferred. When using a cuprous chloride catalyst, themole ratio of cuprous chloride:Grignard reagent may vary from 1:10 up to1:1 with a moleratio range of cuprous chloride:Grignard reagent of 1:8up to 1:2 being preferred.

The reaction may be carried out in the presence of a solvent which isinertto the reaction ingredients such as tetrahydrofuran, toluene anddiethyl ether or mixtures of same. The most preferred solvent is amixture of tetrahydrofuran and toluene. The concentration in moles perliter of solvent may vary from about 1 up to about 5 moles of propionicanhydride per liter of solvent with a preferred concentration ofpropionic anhydrideper liter of solvent being from 2 up to 3 moles ofpropionic anhydride per liter of solvent. When using a mixture oftetrahydrofuran and toluene as the solvent, the volume/volume ratio oftoluene:tetrahydrofuran may vary from 0.1:1 up to 1:0.1 with a preferredvolume/volume ratio of toluene:tetrahydrofuran being from 1:1 up to 3:1.

The time of reaction is measured insofar as the time of addition ofreactants is concerned and time of ageing of reaction mass after theaddition. Thus, the time of addition of reactants may vary from 0.5hours up to 4 hours and the time of ageing may vary from 0.5 up to 4hours. Longer times of reaction give rise to an increase in the overallyield of reaction product but most of the yield of reaction product isrealized after one hour of ageing.

In carrying out the reaction sequence: ##STR29##the mole ratio of MnCl₂:Grignard reagent having the structure: ##STR30##is about 1:1.

The mole ratio of propionyl chloride having the structure:##STR31##organometallic manganese compound having the structure:##STR32##is about 1.1:1.

The temperature of reaction for the reaction of the Grignard reagenthavingthe structure: ##STR33##with MnCl₂ may vary from about 0° C. up to30° C. and the temperature of reaction for the reaction of theorganometallic compound having the structure: ##STR34##with thepropionyl chloride having the structure: ##STR35##may vary from about30° C. up to about 50° C. A solvent should be used in this reactionwhich is inert to the reaction ingredientsand the most preferred solventis diethyl ether. The reaction pressure may vary from 1 up to 2atmospheres depending upon the desired temperature of reaction andsolvent used. Refluxed temperatures are preferred and accordingly,appropriate pressures are to be employed. The time of reaction is afunction of time of addition and time of ageing. The time ofaddition mayvary from 0.5 up to 3 hours and the time of ageing may vary from 1 up to8 hours. The molar concentration of reactant in solvent may vary from 2moles Grignard reagent per liter of solvent used up to about 5moles ofGrignard reagent per liter of solvent used.

In general precedent in the prior art exists for a reaction to make sucha sterically hindered compound such as the compound having thestructure: ##STR36##using the Grignard reagent having the structure:##STR37##and propionic anhydride having the structure:##STR38##particularly in the absence of a catalyst. The steric hindrenceof the starting Grignard reagent gives rise to an expectation of verylow, if notnegligible yield. However, as will be noted by a comparisonof Table 1 (setforth in Example I) and Table 2 (set forth in Example II)the yields of reaction product having the structure: ##STR39##are fargreater using propionic anhydride than when using the propionyl chloridehaving the structure: ##STR40##even when using the manganese chloridereaction product of the Grignard reagent having the structure:##STR41##to react with propionyl chloride having the structure:##STR42##

The following examples are given to illustrate embodiments of myinvention as it is presently preferred to practice it. It will beunderstood that these examples are illustrative and the invention is notto be considered as restricted thereto, except as indicated in theappended claims. Certainexamples set forth in Table 2 of Example II areillustrative of the prior art.

EXAMPLE I PREPARATION OF 2-METHYL-2-PHENYL-4-HEXANONE

Reaction: ##STR43##

Equipment:

5 liter and 12 liter three neck reaction flasks;

Reflux condenser;

Addition funnel;

Y-adapter;

Thermomether;

Bubbler;

Stirrer.

Reagents:

Neophyl chloride, having the structure: ##STR44##1348 g (8 moles);Magnesium 192 g (8 moles);

Propionic anhydride 1248 g (9.6 moles);

Toluene 2100 ml;

Tetrahydrofuran anhydrous 800 ml;

Acetic acid 2000 g.

Procedure:

1. Tetrahydrofuran (800 ml) and magnesium (192 g) are placed in a5-liter three neck reaction flask equipped with a reflux condenser, athermomether, an addition funnel and a stirrer. The system is purgedwith nitrogen to replace air in the system and the static nitrogenblanket is placed throughout the reaction.

2. The resulting mixture is then heated to 65° C.

3. Neophyl cholride (25 g) is added at 65° C. to start the reaction (seeNote 1).

4. After the reaction is commenced, a mixture of neophyl chloride (1323g) and toluene (1600 ml) is added at 55° C.-65° C. over a period of 90minutes.

5. The reaction mixture is stirred at 60° C. for additional 4 hours andthen cooled to room temperature (about 25° C.).

6. Toluene (500 ml), THF (1200 ml) and propionic anhydride are placed ina 12-liter three neck reaction flask fitted with a reflux condenser, athermomether, an addition funnel and a stirrer. The system is flushedwithnitrogen to replace air in the system and the static nitrogenblanket is placed throughout the reaction over the reaction mass.

7. The mixture is cooled to -10° C. (see Note 3).

8. The Grignard reagent solution prepared in step 5 is placed in theaddition funnel (see Note 4) and is added to the solution at -10° C. upto about 0° C. over a period of 5 hours (see Notes 3 and 5).

9. The reaction mixture is stirred at 0° C.-25° C. for for anadditional2 hours. The GLC profile of the reaction product at the end of thistwo-hour period is set forth in FIG. 1, (see Note 6).

10. The reaction mass is poured into 50% aqueous acetic acid solution(4000ml) at 25° C.-35° C. (In view of the high exothermicity of thereaction the mixture is poured very slowly). The mixture is then stirredfor 30 minutes (see Note 7).

11. The organic layer is separated and washed with saturated sodiumbicarbonate solution (1000 ml) until the pH value of the aqueous layerbecomes 7-8; and then with a saturated sodium chloride solution (1000ml).The organic layer weighs 3940 g.

12. The organic layer is distilled on a one-plate 1/2 inch splash columnwith 50 g of Primol® and 0.1 g of Ionox® to yield the followingfractions:

    ______________________________________                                               Vapor    Liquid                                                        Fraction                                                                             Temp.    Temp.    Vacuum Weight                                                                              Product.sup.a                           No.    (°C.)                                                                           (°C.)                                                                           (mm Hg)                                                                              (g.)  (g.)                                    ______________________________________                                        1      32-60    41-100   100-125                                                                              2231  (lites)                                 2       65-166  93-210   3      1577  1257                                    ______________________________________                                        the residue weighs 28 g.                                                      (.sup.a by GLC analysis: 10% SE 30 column, 10' × 1/8' , programmed a    100°-220° C., at 10° C./min.)                        

13. Fraction 2 is then fractionated under 3 mmHg pressure at 2:1 refluxratio using a 18"×1" goodloe packed column and 50 g of Promol® and 0.1 gof Ionox® to give the following fractions:

    ______________________________________                                                  Vapor     Liquid                                                    Fraction  Temp.     Temp.     Weight Product.sup.a                            No.       (°C.)                                                                            (°C.)                                                                            (g)    (g)                                      ______________________________________                                        1, 2      49-79     109-115   133    Lites                                    3         79-91     115-118   86       1                                      4          91-100   118       119     73                                      5-10      100-108   118-156   1140   1122                                     11        108-110   156-205   27      25                                      ______________________________________                                        The residue weighs 36 g.                                                      (Note .sup.a By GLC analysis, 10% SE30 column 10' × 1/8", programmed     at 100° C.-220° C. at 10° C./minute.                

Chemical yield:

1221 g (80% of theory based on neophyl chloride charged)

Using the procedure of this Example, the following runs (Example IB) 1-9are carried out. In certain cases a catalyst, cuprous chloride, Cu₂ Cl₂is used. In certain cases a solvent, diethyl ether is used in place ofthe tetrahydrofuran-toluene mixture. The amount of diethyl ether used isequal to the amount of tetrahydrofuran-toluene mixture.

                                      TABLE 1                                     __________________________________________________________________________    (Example IB)                                                                  (REACTION OF NEOPHYLMAGNESIUM CHLORIDE AND PROPIONIC ANHYDRIDE)               REAGENT MOLE                    REACTION                                      Grignard reagent                Addition   Aging                                 (neophylmagnesium                                                                       Propionic                                                                           Cu.sub.2 Cl.sub.2    Time       Time                                                                             Addition.sup.d                                                                     Yield              Run                                                                              chloride) anhydride                                                                           catalyst                                                                           Solvent Temp.   (hr)                                                                             Temp.   (hr)                                                                             mode (%)                __________________________________________________________________________    1  0.25      0.30  0.25 diethyl ether                                                                         -10° C.-0° C.                                                           1.5                                                                              -10° C.-0°                                                              0.5                                                                              B    60.sup.a           2  0.25      0.30   0.125                                                                             diethyl ether                                                                         -10° C.                                                                        2.5                                                                              -10° C.-0°                                                              2.0                                                                              B    67.sup.a           3  2.00      2.40  1.00 diethyl ether                                                                         -10° C.-0° C.                                                           2.5                                                                              -10° C.-0°                                                              3.0                                                                              B    63.sup.c           4  1.00      1.20  0.50 THF--Toluene                                                                          -10° C.-0° C.                                                           1.5                                                                              0° C.                                                                          3.0                                                                              B    72.sup.b           5  1.00      0.94  0.25 THF--Toluene                                                                          -10° C.-0° C.                                                           0.6                                                                              -10° C.-0°                                                              3.0                                                                              B    80.sup.b           6  1.00      0.94   0.125                                                                             THF--Toluene                                                                          -10° C.-0° C.                                                           3.0                                                                              -10° C.-0°                                                              3.0                                                                              B    74.sup.b           7  0.50      0.47  --   THF--Toluene                                                                          -10° C.-0° C.                                                           0.5                                                                              -10° C.-0°                                                              2.0                                                                              B    77.sup.a           8  8.00      9.60  --   THF--Toluene                                                                          -10° C.-0° C.                                                           2.0                                                                              -10° C.-0°                                                              5.0                                                                              B    80.sup.c           9  1.60      1.92  --   THF--Toluene                                                                          0° C.                                                                          1.0                                                                              0° C.-20°                                                               2.0                                                                              A    63.sup.b           __________________________________________________________________________    NOTES:-                                                                        .sup.a Calculated by GLC analysis on the reaction mixture.                    .sup.b Calculated by GLC analysis on the rushed over materials                (distillation on a oneplate column).                                          .sup.c Calculated by GLC analysis on the fractionated materials.              .sup.c Addition mode:                                                        A  Addition of propionic anhydride to the Grignard reagent.                   B  Addition of the Grignard reagent to the mixture of propionic anhydride      and Cu.sub.2 Cl.sub. 2.                                                  

EXAMPLE II PREPARATION OF 2-METHYL-2-PHENYLHEXENOL

Reaction: ##STR45##

Into a one liter three-neck reaction flask equipped with thermometer,reflux condenser and addition funnel is placed 12 g (0.5 moles) ofmagnesium and 200 ml diethyl ether. Separately, a solution of 85 g (0.5moles) of neophyl chloride in 100 ml diethyl ether is prepared. 10% ofneophyl chloride solution is then added to the magnesium/diethyl ethermixture. The reaction formed from Grignard reagent is commenced usingiodine crystals and a small amount of Vitride®. After the reactionhascommenced the remaining neophyl chloride solution is added over aperiod oftwo hours at gentle reflux. After the addition of the neophylchloride, thereaction mass is refluxed for one hour. The reaction massis then cooled to -10° C. and 63 g of manganese chloride (MnCl₂) isadded slowlyin small portions. The reaction mass is then stirred for aperiod of 2 hours at -10° C.-0° C. Over a period of 30 minutes, 51 g ofpropionyl chloride is added to reaction mass while maintaining it at 0°C. The reaction mass is allowed then to exotherm to 50° C. and thediethyl ether solvent is permitted to evaporate.

300 cc of 10% acetic acid is then added to the reaction mass at 10° C.The reaction mass is then poured into a separatory funnel and iswashedwith saturated sodium carbonate to a pH of 7 followed by three two200 ml portions of sodium chloride.

The reaction mass is dried over anhydrous sodium sulfate, filtered andstripped of solvent to yield a product weighing 77 g.

This material is distilled at 108° C. and 3 mmHg pressure. MNR, IR andmass spectral analysis confirm that the product has the structure:##STR46##

The following table sets forth runs 1-12 utilizing a procedure identicaltothe procedure of the foregoing example. In place of using diethylether andequal volume of tetrahydrofuran/toluene mixture (5050volume/volume) is used. The mode of addition of reactants is varied from(i) addition of MX_(n) (e.g. manganese chloride) to the Grignard reagentfollowed by addition of propionyl chloride or (ii) addition of theGrignard reagent tothe mixture of propionyl chloride and MX_(n) (e.g.manganese chloride).

                                      TABLE 2                                     __________________________________________________________________________    (EXAMPLE IIB)                                                                 (REACTION OF NEOPHYLMAGNESIUM CHLORIDE AND PROPIONYL CHLORIDE)                REAGENT MOLE                   REACTION                                       Grignard reagent               Addition   Aging                                  (neophylmagnesium                                                                       Propionyl                 Time       Time                                                                             Addition.sup.c                                                                     Yield               Run                                                                              chloride) chloride                                                                            MX.sub.n                                                                          Solvent Temp.   (hr)                                                                             Temp.   (hr)                                                                             mode (%)                 __________________________________________________________________________    1  1.0       1.0   --  THF--Toluene                                                                          0° C.                                                                          1.5                                                                              0° C.                                                                          2  B    23.sup.b            2  2.0       2.2   MnCl.sub.2                                                                        THF--Toluene                                                                          -10° C.-35° C.                                                          1.0                                                                              20° C.-35°                                                              1. A    <5.sup.a                               (2.0)                                                      3  2.0       2.2   MnCl.sub.2                                                                        THF--Toluene                                                                          -10° C.-23° C.                                                          2.5                                                                              -10° C.-20°                                                             2. A    <5.sup.a                               (0.2)                                                      4  2.0       2.2   MnCl.sub.2                                                                        THF--Toluene                                                                          0° C.                                                                          2.0                                                                              0° C.                                                                          2  B    36.sup.b                               (0.2)                                                      5  1.0       1.0   MnCl.sub.2                                                                        THF--Toluene                                                                          0° C.                                                                          1.0                                                                              0° C.-34°                                                               4. B    38.sup.b                               (1.1)                                                      6  0.5       0.55  MnCl.sub.2                                                                        diethyl ether                                                                         0° C.                                                                          0.5                                                                              0° C.-50°                                                               1. A    39.sup.a                               (0.5)                                                      7  0.5       0.55  MnCl.sub.2                                                                        diethyl ether                                                                         0° C.                                                                          0.5                                                                              10° C.                                                                         2  A     4.sup.a                               (0.5)                                                      8  0.05      0.05  MnCl.sub.2                                                                        diethyl ether                                                                         0° C.                                                                          0.1                                                                              0° C.                                                                          4  B    16.sup.a                               (0.005)                                                    9  1.0       1.0   ZnCl.sub.2                                                                        THF--Toluene                                                                          0° C.                                                                          0.5                                                                              0° C.                                                                          8  B    12.sup.a                               (1.0)                                                      10 0.05      0.05  NiBr.sub.2                                                                        THF--Toluene                                                                          0° C.-5° C.                                                             0.5                                                                              0° C.                                                                          4  B    36.sup.a                               (0.005)                                                    11 0.5       0.55  Cu.sub.2 Cl.sub.2                                                                 THF--Toluene                                                                          -10° C.                                                                        0.5                                                                              -10° C.-20°                                                             15 A    30.sup.a                               (0.25)                                                     12 0.5       0.5   Cu.sub.2 Cl.sub.2                                                                 THF--Toluene                                                                          0° C.                                                                          1.0                                                                              0° C.-25°                                                               4. B    48.sup.a                               (0.25)                                                     __________________________________________________________________________    NOTES:                                                                         .sup.a Calculated by GLC analysis on the reaction mixture.                    .sup.b Calculated by GLC analysis on the rushed over materials (distilled     on a oneplate column).                                                        .sup.c Addition mode:                                                        A  Addition of MX.sub.n to the Grignard reagent followed by addition of        propionyl chloride.                                                          B  Addition of the Grignard reagent to the mixture of propionyl chloride       and MX.sub.n                                                             

What is claimed is:
 1. A process for preparing2-methyl-2-phenyl-4-hexanone having the structure: ##STR47## comprisingthe step of intimately admixing propionic anhydride having thestructure: ##STR48## with neophymagnesium chloride having the structure:##STR49## in the presence of an inert solvent selected from the groupconsisting of diethylether, toluene and tetrahydrufuran, the reactiontaking place in the presence of or in the absence of a cuprous chloridecatalyst; the mole ratio of propionic anhydride:neophylmagnesiumchloride being from 0.5:1 up to about 2:1; the temperature of reactionbeing from -10° C. up to 0° C.; the concentration of propionic anhydridein solvent being from about 1 up to about 5 moles of propionic anhydrideper liter of solvent; the time of addition of one reactant to the othervarying from 0.5 hours up to 4 hours and the time of aging of thereaction mass being from 0.5 up to 4 hours.